Description of Research:
Pemphigus vulgaris (PV) is a potentially fatal disorder in which autoantibodies against desmosomal cell adhesion molecules known as desmogleins cause blistering of the skin and mucous membranes. Our laboratory is interested in better understanding pathogenic mechanisms in this model organ-specific autoimmune disease, from both the immunologic and cell biologic perspectives.

A fundamental question in organ-specific autoimmune disease is why the immune system breaks tolerance against only a limited number of self-antigens. We have cloned anti-desmoglein monoclonal antibodies from PV patients to understand how they developed desmoglein autoreactivity. Genetic analysis shows that a limited number of antibody genes encode the human PV autoantibody repertoire and that there is shared VH1-46 gene usage even among different PV patients. PV antibodies using VH1-46 are autoreactive to the disease antigen in the absence of somatic mutation or require very few mutations to develop autoreactivity. Common gene usage indicates a common mechanism for developing autoimmunity in PV. Ultimately, shared structural elements of the PV autoantibody repertoire (e.g., VH or CH gene usage) may lead to safer targeted therapies for pemphigus. Ongoing projects aim to identify potential foreign antigenic triggers of the desmoglein autoimmune response in pemphigus, and to identify the B cell subsets that produce the pathogenic autoantibodies.

The human pathogenic and non-pathogenic anti-desmoglein monoclonal antibodies we have identified are unique reagents that allow for the controlled study of desmosomal cell adhesion in keratinocytes. We have shown that pathogenic anti-desmoglein antibodies prevent desmosome assembly in human keratinocytes by internalizing newly synthesized desmoglein 3, but not its presumed cellular binding partner desmocollin 3. Current studies are examining the role of cell signaling pathways, specifically the p38 MAPK/MK2 axis, in disease pathogenesis.